Bicyclic cannabinoid agonists for the cannabinoid receptor

ABSTRACT

Novel polycyclic cannabinoid analogs are presented which have preferentially high affinities for the cannabinoid CB2 receptor sites. The improved receptor affinity makes these analogs therapeutically useful as medications in individuals and animals for treatment of pain, glaucoma, epilepsy, nausea associated with chemotherapy.

This application is the National Stage of International Application No.PCT/US00/41238, filed Oct. 18, 2000, which claims the benefit of U.S.Provisional Application No. 60/160,239, filed Oct. 18, 1999.

FIELD OF THE INVENTION

The present invention relates generally to cannabinoid compounds and ismore particularly concerned with new and improved cannabinoid compoundsexhibiting high binding affinity and selectivity for the CB1 and CB2cannabinoid receptors, pharmaceutical preparations employing theseanalogs and methods of administering therapeutically effective amountsof the preparations to provide a physiological effect.

BACKGROUND OF THE INVENTION

Classical cannabinoids such as the marijuana derived cannabinoidΔ⁹-tetrahydrocannabinol, (Δ⁹-THC) produce their pharmacological effectsthrough interaction with specific cannabinoid receptors in the body. Sofar, two cannabinoid receptors have been characterized: CB1, a centralreceptor found in the mammalian brain and peripheral tissues and CB2, aperipheral receptor found only in the peripheral tissues. Compounds thatare agonists or antagonists for one or both of these receptors have beenshown to provide a variety of pharmacological effects. See, for example,Pertwee, R. G., Pharmacology of cannabinoid CB1 and CB2 receptors,Pharmacol. Ther., (1997) 74:129-180 and Di Marzo, V., Melck, D.,Bisogno, T., DePetrocellis, L., Endocannabinoids: endo-genouscannabinoid receptor ligands with neuromodulatory action, TrendsNeurosci. (1998) 21:521-528.

There is considerable interest in developing cannabinoid analogspossessing high affinity for one of the CB1 or CB2 receptors. Suchanalogs may offer a rational therapeutic approach to a variety ofdisease states.

SUMMARY OF THE INVENTION

The inventive compounds have been found to act as agonists for the CB1and CB2 receptors. The invention includes compounds selective for eitherthe CB1 or CB2 receptors. Certain of the novel bicyclic cannabinoidspossess surprisingly improved cannabinoid receptor affinity and/orspecificity over known cannabinoids. Thus, one aspect of the inventionis the novel cannabinoids represented by structural formula 1 andphysiologically acceptable salts thereof.

-   -   wherein R₁ is selected from OH; H; OCH₃; N₃; NH₂;        O(CH₂)_(n)N(CH₃)₂ and    -    where n is an integer from 1-3;    -   R₂ is selected from (CH₂)_(n)CH₃, where n is an integer from        4-6; C(CH₃)₂(CH₂)_(n)CH₃, where n is an integer from 3-5;    -    where each X is independently selected from C, O, S and NH and        n is an integer from 3-5; (CH₂)_(n)C≡CH where n is an integer        from about 3-5; C≡C(CH₂)_(n)CH₃ where n is an integer from 2-4        and    -    where R is (CH₂)_(n)CH₃, where n is a maximum of 7; and    -   R₃ is selected from H; OH; OCH₃; N₃ and O(CH₂)_(n)OH; where n is        an integer from 1-3.

The novel cannabinoids are also more polar (less lipophilic) then knowncannabinoids, which can improve their therapeutic usefulness in certainapplications. Therefore, the novel compounds described herein, andphysiologically acceptable salts thereof, represent potentially usefulmaterials for providing a physiological effect to treat pain; peripheralpain; neuropathic pain; glaucoma; epilepsy; nausea such as associatedwith cancer chemotherapy; AIDS Wasting Syndrome; cancer;neurodegenerative diseases including Multiple Sclerosis, Parkinson'sDisease, Huntington's Chorea and Alzheimer's Disease; to enhanceappetite; to reduce fertility; to prevent or reduce diseases associatedwith motor function such as Tourette's syndrome; to prevent or reduceinflammation; to provide neuroprotection and to suppress memory andproduce peripheral vasodilation. Thus, another aspect of the inventionis the administration of a therapeutically effective amount of aninventive compound, or a physiologically acceptable salt thereof, to anindividual or animal to provide a physiological effect.

DESCRIPTION OF SOME PREFERRED EMBODIMENTS

As used herein a “therapeutically effective amount” of a compound, isthe quantity of a compound which, when administered to an individual oranimal, results in a sufficiently high level of that compound in theindividual or animal to cause a discernible increase or decrease instimulation of cannabinoid receptors. Physiological effects that resultfrom cannabinoid receptor stimulation include analgesia, decreasednausea resulting from chemotherapy, sedation and increased appetite.Other physiological functions include relieving intraocular pressure inglaucoma patients and suppression of the immune system. Typically, a“therapeutically effective amount” of the compound ranges from about 10mg/day to about 1,000 mg/day.

As used herein, an “individual” refers to a human. An “animal” refersto, for example, veterinary animals, such as dogs, cats, horses and thelike, and farm animals, such as cows, pigs and the like.

The compound of the present invention can be administered by a varietyof known methods, including orally, rectally, or by parenteral routes(e.g., intramuscular, intravenous, subcutaneous, nasal or topical). Theform in which the compounds are administered will be determined by theroute of administration. Such forms include, but are not limited to,capsular and tablet formulations (for oral and rectal administration),liquid formulations (for oral, intravenous, intramuscular; orsubcutaneous administration) and slow releasing microcarriers (forrectal, intramuscular or intravenous administration). The formulationscan also contain a physiologically acceptable vehicle and optionaladjuvants, flavorings, colorants and preservatives. Suitablephysiologically to acceptable vehicles may include, for example, saline,sterile water, Ringer's solution, and isotonic sodium chloridesolutions. The specific dosage level of active ingredient will dependupon a number of factors, including, for example, biological activity ofthe particular preparation, age, body weight, sex and general health ofthe individual being treated.

The novel cannabinoids can generally be described with reference tostructural formula 1 and physiologically acceptable salts thereof.

-   -   wherein R₁ is selected from OH; H; OCH₃; N₃; NH₂; O(CH₂) N(CH₃)₂        and    -    where n is an integer from 1-3;    -   R₂ is selected from (CH₂)_(n)CH₃, where n is an integer from        4-6; C(CH₃)₂(CH₂)_(n)CH₃, where n is an integer from 3-5;    -    where each X is independently selected from C, O, S and NH and        n is an integer from 3-5; (CH₂)_(n)C≡CH where n is an integer        from about about 3-5; C≡C(CH₂)_(n)CH₃ where n is an integer from        2-4 and    -    where R is (CH₂)_(n)CH₃, where n is a maximum of 7; and    -   R₃ is selected from H; OH; OCH₃; N₃ and O(CH₂)_(n)OH; where n is        an integer from 1-3.

The following examples are given for purposes of illustration only inorder that the present invention may be more fully understood. Theseexamples are not intended to limit in any way the practice of theinvention. Material AM1703was prepared. Material AM1703 can berepresented by structural formula 1 when R₁ and R₃ are each OH and R₂ is1,1-dimethylheptyl. Material AM1703 is shown in structural formula 2.

-   -   Material AM1703 was prepared as follows.        [7-(3,5-Dimethoxyphenyl-1,3-dithian-7-yl)-1-heptynyl]trimethysilane.

A solution of 5 g (19.5 mmol) of 2-(3,5-dimethoxyphenyl)-1,3-dithiane in38 mL of dry tetrahydrofuran was cooled to −30° C. under argon and 14.5mL of a 1.6 M solution (23.5 mmol) of n-butyllithium in hexanes wasadded dropwise. The yellow-brown reaction mixture was stirred at thesame temperature for 2 hours (h) and 5.43 g (23.4 mmol, neat) of(6-bromo-1-hexynyl)trimethysilane was added in a dropwise manner whenthe color changed from yellow-brown to light yellow. The reactionmixture was allowed to warm to room temperature overnight and pouredinto water and extracted with diethyl ether. The combined organicextracts were dried and ether removed to afford the crude product whichwas purified on silica gel (15% diethyl ether-petroleum ether) to afford6.81 g (86%) of the title compound as an oil. Anal. calcd. forC₂₁H₃₂O₂S₂Si C, 61.72; H, 7.89.

[7-(3,5-Dimethoxyphenyl)-7-oxo-1-heptynyl]trimethylsilane.

A solution of 6.40 g (15.8 mmol) of[7-(3,5-dimethoxyphenyl-1,3-dithian-7-yl)-1-heptynyl]trimethysilane in160 mL of 10% aqueous methanol was cooled in an ice-bath and 10.2 g(23.7 mmol, 1.5 equiv.) of bis(trifluoroacetoxy)iodobenzene was addedportionwise with stirring. The reaction mixture was stirred for anadditional 10 min and poured into 100 mL of sodium bicarbonate solution.The mixture was extracted with diethyl ether, ether extracts werecombined, dried and ether removed to afford an oil which waschromatographed on silica gel to afford 4.5 g (90%) of the titlecompound. Anal. calcd. for C₁₈H₂₆O₃Si C, 67.88; H, 8.23.

[7-(3,5-Dimethoxyphenyl)-7-methyl-1-octynyl]trimethysilane.

[7-(3,5-Dimetho-xyphenyl)-7-oxo-1-heptynyl]trimethysilane (1.50 g, 4.75mmol) was dissolved in 10 mL of anhydrous ether, the solution was cooledin an ice-bath under argon and a 3.16 mL of a 3 M solution ofmethylmagnesium bromide (9.48 mmol) in ether was added dropwise. Thelight grey solution was allowed to warm to room temperature and stirredfor an additional hour. The reaction mixture was poured into saturatedammonium chloride solution, the organic phase was separated and theaqueous phase was extracted with fresh diethyl ether. The combined etherextracts were dried and ether removed to afford 1.50 g (95%) of pure[7-(3,5-dimethoxyphenyl)-7-hydroxy-1-octynyl]trimethysilane as a viscousoil after passing through a short silica gel column.

The above tertiary carbinol (1.50 g, 4.52 mmol) was dissolved in 9 mL ofanhydrous carbon tetrachloride and dry hydrogen chloride gas was bubbledthrough for 1 h. The solution was transferred to a separatory funnelwith the aid of more carbon tetrachloride, washed with water and 10%sodium bicarbonate solution. The organic phase was dried and rotaryevaporated to afford an oil which was passed through a short silicacolumn to give 1.43 g (90%) of the pure[7-chloro-7-(3,5-dimethoxyphenyl)-1-octynyl]trimethysilane.

A solution of the above chloride (1.43 g, 4.08 mmol) in dry toluene wascooled to −30° C. under argon and 4.1 mL of a 2 M solution oftrimethylaluminum in toluene was added in a slow dropwise manner. Theresulting clear reaction mixture was stirred at room temperature forabout 16 hours and then 5% aqueous hydrochloric acid was added in a verycautious manner. The organic layer was separated, washer with water,dried and toluene removed. The residual oil was chromatographed onsilica gel to afford a colorless oil. Anal. calcd. for C₂₀H₃₂O₂Si C,72.23; H, 9.70.

7-(3,5-Dimethoxyphenyl)-7-methyl-1-octyne (8-065).

[7-(3,5-Dimethoxyphenyl)-7-methyl-1-octynyl]trimethysilane (900 mg, 2.73mmol) was dissolved in 3.5 mL of anhydrous methanol. Anhydrous potassiumcarbonate (75 mg, 0.55 mmol, 20 mol %) was added and the heterogeneousmixture was stirred at room temperature, under argon, for 24 h. Thereaction mixture was diluted with water and extracted with diethylether. The ether extract was dried, concentrated by rotary evaporationand the residue was purified by chromatography on silica gel (5% ethylether-petroleum ether) to give 540 mg (76%) of the desilylated product.Anal. calcd. for C₁₇H₂₄O₂ C, 78.42; H, 9.29.

3-(1,1-Dimethylhept-6-ynyl)resorcinol (8-065).

A solution of 7-(3,5-dimethoxyphenyl)-7-methyl-1-octyne (445 mg, 1.71mmol) in 17 mL of anhydrous dichloromethane was cooled to −40° C. underargon and 4.3 mL of a 1 M solution of boron tribromide (4.30 mmol) wasadded via syringe. The reaction mixture was allowed to warm to 0° C.with stirring over a period of 1-1.5 h and then quenched with saturatedsodium bicarbonate. The organic layer was separated, dried and solventremoved. The residue was chromatographed on silica gel (30-40% ethylether-petroleum ether) to give 224 mg (56%) of the title resorcinol.Anal. calcd. for C₁₅H₂₀O₂ C, 77.55; H, 8.68.

Coupling of 3-(1,1-Dimethylhept-6-ynyl)resorcinol with NopinoneDiacetate.

A mixture of 224 mg (0.97 mmol) of3-(1,1-dimethylhept-6-ynyl)resorcinol, 270 mg (0.97 mmol) nopinonediacetate and 185 mg (0.97 mmol) of p-toluenesulfonic acid monohydratein 10 mL of chloroform was allowed to stand at room temperature for 4 has described by Archer et al. After confirming the completion of thereaction by TLC, the reaction mixture was transferred to a separatoryfunnel and washed successively with 10% sodium bicarbonate, water, anddried. Solvent was removed and the residue was purified by flashchromatography on silica gel (30-40% ethyl ether- petroleum ether) togive 140 mg (40%) of the title bicyclic ketone (AM1703).

As used herein, “binding affinity” (K_(i)) is represented by the IC₅₀)value which is the concentration of an analog required to occupy the 50%of the total number (Bmax) of the receptors. The lower the IC₅₀ valuethe higher the binding affinity. As used herein an analog is said tohave “binding selectivity” if it has higher binding affinity for onereceptor compared to the other receptor; e.g. a cannabinoid analog whichhas an IC₅₀ of 0.1 nanomoles (nM) for CB1 and 10 nM for CB2, is 100times more selective for the CB1 receptor. The AM1703 material wastested for CB2 receptor binding affinity and for CB1 receptor affinity(to determine selectivity for the CB2 receptor).

For the CB1 receptor binding studies, membranes were prepared from ratforebrain membranes according to the procedure of P. R. Dodd et al, ARapid Method for Preparing Synaptosomes: Comparison with AlternativeProcedures, Brain Res., 107-118 (1981). The binding of the novelanalogues to the CB1 cannabinoid receptor was assessed as described inW. A. Devane et al, Determination and Characterization of a CannabinoidReceptor in a Rat Brain, Mol. Pharmacol., 34, 605-613 (1988) and A.Charalambous et al, 5′-azido Δ″-THC: A Novel Photoaffinity Label for theCannabinoid Receptor, J. Med. Chem., 35, 3076-3079 (1992) with thefollowing changes. The above articles are incorporated by referenceherein.

Membranes, previously frozen at −80° C., were thawed on ice. To thestirred suspension was added three volumes of TME (25 mM Tris-HClbuffer, 5 mM MgCl₂ and 1 mM EDTA) at a pH 7.4. The suspension wasincubated at 4° C. for 30 min. At the end of the incubation, themembranes were pelleted and washed three times with TME.

The treated membranes were subsequently used in the binding assaydescribed below. Approximately 30 μg of membranes were incubated insilanized 96-well microtiter plate with TME containing 0.1% essentiallyfatty acid-free bovine serum albumin (BSA), 0.8 nM [³] CP-55,940, andvarious concentrations of test materials at 30° C. for 1 hour. Thesamples were filtered using Packard Filtermate 196 and Whatman GF/Cfilterplates and washed with wash buffer (TME containing 0.5% BSA).Radioactivity was detected using MicroScint 20 scintillation cocktailadded directly to the dried filterplates, and the filterplates werecounted using a Packard Instruments Top-Count. Nonspecific binding wasassessed using 100 nM CP-55,94b. Data collected from three independentexperiments performed with duplicate determinations was normalizedbetween 100% and 0% specific binding for [³H] CP-55,940, determinedusing buffer and 100 nM CP-55,940. The normalized data was analyzedusing a 4-parameter nonlinear logistic equation to yield IC₅₀ values.Data from at least two independent experiments performed in duplicatewas used to calculate IC₅₀ values which were converted to K₁ valuesusing the using the assumptions of Cheng et al, Relationship Between theInhibition Constant (K ₁) and the concentration of Inhibitor whichcauses 50% Inhibition (IC ₅₀) of an Enzymatic Reaction, Biochem.Pharmacol., 22, 3099-3102, (1973), which is incorporated by referenceherein.

For the CB2 receptor binding studies, membranes were prepared fromfrozen mouse spleen essentially according to the procedure of P. R. Doddet al, A Rapid Method for Preparing Synaptosomes: Comparison withAlternative Procedures, Brain Res., 226, 107-118 (1981) which isincorporated by reference herein. Silanized centrifuge tubes were usedthroughout to minimize receptor loss due to adsorption. The C82 bindingassay was conducted in the same manner as for the CB1 binding assay.

Binding affinities (K_(i)) for both the CB1 and CB2 receptors aretypically expressed in nanomoles (nM), although novel compound AM1703surprisingly exhibited a CB2 affinity of 0.59 picomoles (pM) and about a500-fold CB2 selectivity over CB1. Other cannabinoid analogs have beenreported that show some selectivity for the CB2 receptor. However theinventive analog described herein has surprisingly high affinity andselectivity for the CB2 receptor.

The physiological and therapeutic advantages of the inventive materialscan be seen with additional reference to the following references, thedisclosures of which are hereby incorporated by reference. Arnone M.,Maruani J., Chaperon P, et al, Selective inhibition of sucrose andethanol intake by SR141716, an-antagonist of central cannabinoid (CB1)receptors, Psychopharmacal, (1997) 132, 104-106. Colombo G, Agabio R,Diaz G. et al: Appetite suppression and weight loss after thecannabinoid antagonist SR141716. Life Sci. (1998) 63-PL13-PL117. SimiandJ, Keane M, Keane P E, Soubrie P: SR 141716, A CB1 cannabinoid receptorantagonist, selectively reduces sweet food intake in marmoset. Behav.Pharmacol (1998) 9:179-181. Brotchie J M: Adjuncts to dopaminereplacement a pragmatic approach to reducing the problem of dyskinesi inParkinson's disease. Mov. Disord. (1998) 13:871-876. Terranova J-P,Storme J-J Lafon N et al: Improvement of memory in rodents by theselective CB1 cannabinoid receptor antagonist. SR 141716.Psycho-pharmacol (1996) 126:165-172. Hampson A L Grimaldi M. Axpirod J.Wink D: Cannabidiol and (−) Δ⁹ tetrahydrocannabinol are neuroprotectiveantioxidants. Proc. Natl. Acad. Sci. USA (1998) 9S:8268-8273. Buckley NE, McCoy K I, Mpzey E et al Immunomodulation by cannabinoids is absentin mice deficient for the cannabinoid CB ₂ receptor. Eur. J. Pharmacol(2000) 396:141-149. Morgan Dr: Therapeutic Uses of Cannabis. HarwoodAcademic Publishers, Amsterdam. (1997). Joy J E, Wagtson S J, Benson JA: Marijuana and Medicine Assessing the Science Base. National AcademyPress, Washington, D.C., USA (1999). Shen M. Thayer SA: Cannabinoidreceptor agonists protect cultured rat hippocampal neurons fromexcitotoxicity. Mol. Pharmacol (1996) 54:459-462. DePetrocellis L, MelckD, Palmisano A. et al: The endogenous cannabinoid anandamide inhibitshuman breast cancer cell proliferation. Proc Natl. Acad. Sci USA (1998)95:8375-8380. Green K. Marijuana smoking vs. cannabinoids for glaucomatherapy. Arch. Ophibalmol. (1998) feb 433-1437. Hemming M, YellowleesPM, Effective treatment of Tourette's syndrome with marijuana. J.Psychopharmacol, (1993) 7:389-391. Muller-Vahl KB, Schneider U, Kolbe H,Emrich, H M. Treatment of Tourette's svndrome withdelta-9-tetrahydrocannabinol. Am. J. Psychiat. (1999) 156-195.Muller-Vahl KB, Kolbe H, Schneider U, Emrich, HM Cannabis in movementdisorders. Porsch. Kompicmentarmed (1999) 6 (suppl. 3) 23-27. Consroe P,Musty R, Rein J, Tillery W, Pertwee R. The perceived effects of smokedcannabis on patents with multiple sclerosis, Eur. Neurol. (1997)38-44-48. Pinnegan-Ling D, Musty R. Marinol and Phantom limb pain: acase study. Proc Inv. Cannabinoid Rea. Sec. (1994):53. Brenneisen R,Pgli A, Elsohly M A, Henn V. Spiess Y: The effect of orally and rectallyadministered Δ ⁹ -tetrahydrocannabinol, on spasticity, a pilot studywith 2 patients. Int. J. Clin Pharmacol Ther. (1996) 34:446-452. MartynCN. Illis L S, Thom J. Nabilone in the treatment of multiple sclerosis.Lancet (1995) 345:579. Maurer M, Henn V, Dittrich A, Hofmann A.Delta-9-tetrahydrocannabinol shows antispastic and analgesic effects ina single case double-blind trial. Eur. Arch. Psychiat. Clin. Neurosci.(1990), Z40:1-4. Herzberg U, Eliav E, Bennett G J, Kopin I J: Theanalgesic effects of R(+) WIN 55,212-2mesylate, a high affinitycannabinoid agonist in a rare model of neuropathic pain, Neurosci.Letts. (1997) 221:157-160. Richardson J D, Kilo S. Hargreaves K M,Cannabinoids reduce dryperalgesia and inflammation via interaction withperipheral CB1 receptors. Pain (1998) 75:111-119. Richardson J D,Aanonsen I, Hargreaves K M: Antihyperalgesic effects of a spinalcannabinoids. Eur. J. Pharmacol. (1998) 346:145-153. Calignano A, LaRana G. Diuffrida A, Piomelli D: Control of pain initiation byendogenous cannabinoids. Nature (1998) 394:277-291. Wagner J A, Varga K,Jarai Z, Kunos G: Mesenteric vasodilation mediated by endotheliaanandamide receptors. Hypertension (1999) 33:429-434. Schuel, H.,Burkman, L. J., Picone, R. P., Bo, T., Makriyannis, A., Cannabinoidreceptors in human sperm. Mol. Biol. Cell., (1997) (8), 325a.

The inventive analogs described herein, and physiologically acceptablesalts thereof, have high potential when administered in therapeuticallyeffective amounts for providing a physiological effect useful to treatpain; peripheral pain; glaucoma; epilepsy; nausea such as associatedwith cancer chemotherapy; AIDS Wasting Syndrome; cancer;neurodegenerative diseases including Multiple Sclerosis, Parkinson'sDisease, Huntington's Chorea and Alzheimer's Disease; to enhanceappetite; to reduce fertility; to prevent or reduce diseases associatedwith motor function such as Tourette's syndrome; to prevent or reduceinflammation; to provide neuroprotection and to suppress memory andproduce peripheral vasodilation. Thus, another aspect of the inventionis the administration of a therapeutically effective amount of aninventive compound, or a physiologically acceptable salt thereof, to anindividual or animal to provide a physiological effect.

Those skilled in the art will recognize, or be able to ascertain with nomore than routine experimentation, many equivalents to the specificembodiments of the invention disclosed herein. Such equivalents areintended to be encompassed by the scope of the invention.

1. A compound of the formula

and physiologically acceptable salts of the compound, wherein: R₁ isselected from OH; H; OCH₃; N₃; NH₂; O(CH₂)_(n)N(CH₃)₂ and

 where n is an integer from 1-3; R₃ is selected from H; OH; OCH₃; N₃ andO(CH₂)_(n)OH; where n is an integer from 1-5; and R₂ is selected from(CH₂)_(n)C≡CH where n is an integer from 3-5, C≡C(CH₂)_(n)CH₃ where n isan integer from 2-4,

 where each X is independently selected from CH₂, O, S and NH and n isan integer from 3-5,

where R is (CH₂)_(n)CH₃ and n is a maximum of 7, C(CH₃)₂(CH₂)_(n)CH₃,where n is an integer from 3-5, and (CH₂)_(n)CH₃, where n is an integerfrom 4-6; with the provisos that: R2 cannot be C(CH₃)₂(CH₂)_(n)CH₃,where n is an integer from 3-5 when R₁ and R₃ are both OH, R2 cannot be(CH₂)_(n)CH₃, where n is an integer from 4-6 when one of R₁ or R₃ is Hand the other of R₁ or R₃ is OCH₃, and R2 cannot be (CH₂)_(n)CH₃, wheren is an integer from 4-6 when R₁ and R₃ are both OH.
 2. The compound ofclaim wherein 1 wherein R₂ is selected from (CH₂)_(n)C≡CH where n is aninteger from 3-5, C≡C(CH₂)_(n)CH₃ where n is an integer from 2-4,

where each X is independently selected from CH₂, O, S and NH and n is aninteger from 3-5, and

where R is H or (CH₂)_(n)CH₃ and n is a maximum of
 7. 3. The compound ofclaim 1 wherein R₁ and R₃ are each OH and R₂ is selected from(CH₂)_(n)C≡CH where n is an integer from 3-5, C≡C(CH₂)_(n)CH₃ where n isan integer from 2-4,

where each X is independently selected from CH₂, O, S and NH and n is aninteger from 3-5, and

where R is H or (CH₂)_(n)CH₃ and n is a maximum of
 7. 4. The compound ofclaim 1 wherein: R₁ is selected from OH; NH₂; O(CH₂)_(n)N(CH₃)₂ and

 where n is an integer from 1-3; R₂ is selected fromC(CH₃)₂(CH₂)_(n)CH₃, where n is an integer from 3-5;

 where each X is independently selected from CH₂O, S and NH and n is aninteger from 3-5; and

 and where R is H, (CH₂)_(n)CH₃, and n is a maximum of 7; and R₃ isselected from H; OH; OCH₃ N₃ and O(CH₂)_(n)OH; where n is an integerfrom 1-5.
 5. A method of preferentially stimulating the CB2 receptors inan individual or animal comprising administering to the individual oranimal a therapeutically effective amount of a compound having theformula:

and physiologically acceptable salts of the compound, wherein R₁ isselected from OH; H; OCH₃; N₃; NH₂; O(CH₂)_(n)N(CH₃)₂ and

where n is an integer from 1-3; R₂ is selected from (CH₂)_(n)CH₃, wheren is an integer from 4-6; C(CH₃)₂(CH₂)_(n)CH₃, where n is an integerfrom 3-5;

 where each X is independently selected from CH₂, O, S and NH and n isan integer from 3-5; (CH₂)_(n)C≡CH where n is an integer from 3-5;C≡C(CH₂)_(n)CH₃ where n is an integer from 2-4 and

 where R is (CH₂)_(n)CH₃, and n is a maximum of 7; and R₃ is selectedfrom H; OH; OCH₃; N₃ and O(CH₂)_(n)OH; where n is an integer from 1-5.6. The method of claim 5 wherein R₁ and R₃ are each OH and R₂ is1,1-dimethylheptyl.
 7. The method of claim 5 wherein: R₁ is selectedfrom OH; NH₂; O(CH₂)_(n)N(CH₃)₂ and

 where n is an integer from 1-3; R₂ is selected fromC(CH₃)₂(CH₂)_(n)CH₃, where n is an integer from 3-5;

 where each X is independently selected from CH₂, O, S and NH and n isan integer from 3-5; and

 where R is H, (CH₂)_(n)CH₃, and n is a maximum of 7; and R₃ is selectedfrom H; OH; OCH; N₃ and O(CH₂)_(n)OH; where n is an integer from 1-5. 8.The method of claim 5 wherein R₂ is selected from (CH₂)_(n)C≡CH where nis an integer from 3-5, C≡C(CH₂)_(n)CH₃ where n is an integer from 2-4,

where each X is independently selected from CH₂, O, S and NH and n is aninteger from 3-5, and

where R is H or (CH₂)_(n)CH₃ and n is a maximum of
 7. 9. Apharmaceutical composition containing a therapeutically effective amountof a compound having the formula:

and physiologically acceptable salts of the compound, wherein R₁ isselected from OH; H; OCH₃; N₃; NH₂; O(CH₂)_(n)N(CH₃)₂ and

where n is an integer from 1-3; R₂ is selected from (CH₂)_(n)CH₃, wheren is an integer from 4-6; (CH₃)₂(CH₂)_(n)CH₃, where n is an integer from3-5;

 where each X is independently selected from CH₂, O, S and NH and n isan integer from 3-5; (CH₂)_(n)C≡CH where n is an integer from 3-5;C≡C(CH₂)_(n)CH₃ where n is an integer from 2-4 and

 where R is H, (CH₂)_(n)CH₃, and n is a maximum of 7; and R₃ is selectedfrom H; OH; OCH₃; N₃ and O(CH₂)_(n)OH; where n is an integer from 1-5.10. The pharmaceutical composition of claim 9 wherein: R₁ is selectedfrom OH; NH₂; O(CH₂)_(n)N(CH₃)₂ and

where n is an integer from 1-3; R₂ is selected from C(CH₃)₂(CH₂),CH₃,where n is an integer from 3-5;

 where each X is independently selected from CH₂, O, S and NH and n isan integer from 3-5; and

 where R is H, (CH₂)_(n)CH₃, and n is a maximum of 7; and R₃ is selectedfrom H; OH; OCH₃; N₃ and O(CH₂)_(n)OH; where n is an integer from 1-5.11. The pharmaceutical composition of claim 9 wherein R₂ is selectedfrom (CH₂)_(n)C≡CH where n is an integer from 3-5, C≡C(CH₂)_(n)CH₃ wheren is an integer from 2-4,

where each X is independently selected from CH₂, O, S and NH and n is aninteger from 3-5, and

where R is H or (CH₂)_(n)CH₃ and n is a maximum of 7.